Oral-History:Nicholas Peppas

About Nicholas Peppas

Peppas was born in Athens in 1948. He received his first diploma from the National Technical University of Athens in 1971, then went to MIT for graduate study in biomedical engineering, PhD in 1973. He has taught at Purdue University since 1976, and in 1998 helped set up a discrete department of Biomedical Engineering there. His research has included the development of non-thrombogenic, heparinized biomaterials (materials that don’t make blood clot), benign manufacturing of biomaterials by multiple freezings and thawings (which means no toxins are added in the manufacturing process), understanding the mechanisms of arteriosclerosis, gels, biomaterials for artificial kidneys, drug delivery, smart gels and materials, molecular design, bioadhesives materials, pH systems, smart hydrogel systems, and temperature sensitive systems. He became the editor of Biomaterials in 1982. He has also done research on the history of chemical engineering and on the middle Byzantine Empire.

Peppas worked under Ed Merrill, Ed Salzmann, and Eugene Stanley, and has collaborated with Alan Rebar, Les Geddes, Steve Ash, Robert Gurny, and Bob Langer. Other people of note in the field include Wilhelm Kolff, Jarvik, Alan Michaels, Alan Hoffman, Clark Colton, Doug Laufenberger, Bob Nerem, Paul Galetti, Ed Leonard, and Mitch Lett. He descibes the history of chemical engineering from practical/industrial to quantitative to mathematical, and, with modern computers, sees it moving towards bioengineering, particularly metabolic engineering. Biomedical engineering in particular is working on biochips, bionanotechnology, the combination of electronics and drug delivery.

About the Interview

Interview #405 for the IEEE History Center, The Institute of Electrical and Electronics Engineering, Inc.

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Interview

Childhood, family, and educational background

Nebeker:

Would you tell us where and when you were born and a little about the family you came from?

Peppas:

I was born in Athens, Greece, in 1948. My family was a family of professors. My mother’s family was originally German, from Göttingen, and my grandfather, great grandfather, and great-great grandfather were all professors.

Nebeker:

What a long line of professors!

Peppas:

My grandparents met in Germany and then came to Greece, and then of course the children were born in Greece. So I got Greek and German education at the same time.

Nebeker:

And you came from an academic environment.

Peppas:

It was an academic background. I remember that from the very early days, they wanted me to become a professor.

Nebeker:

You said that history was a prospect.

Peppas:

Yes. There were several archeologists and a historian in the family. It was only natural to use them as role models. In fact, my great grandfather was a professor of archeology at the University of Athens. However, in the ‘60s I decided that engineering, and chemical engineering specifically, would be more appropriate.

Peppas' research in history and the history of engineering

Nebeker:

But you have not forgotten history. You told me you have written many articles.

Peppas:

I do write about specific aspects of history and still do research in the field.

Nebeker:

Just for the record, what is your area of interest in history?

Peppas:

My main interest is the Byzantine Empire based in Constantinople, especially the period of 950 to 1025, which is in the middle of a series of emperors that we know as the Macedonian Dynasty. This was a very strong period for the empire, but probably its last major height. The Byzantine Empire continued from about 1028 until 1453 when it fell.

Nebeker:

But you've also done history of chemical engineering.

Peppas:

Well, just mostly as a hobby. I was very interested first in collecting information about Purdue University and its contributions to engineering, because, as you know, Purdue is one of the leading engineering schools in the world and the country, especially in chemical engineering.

I wanted to collect information and write about how chemical engineering developed here at Purdue and what Purdue’s contributions have been to the field. This led to the book I published in 1986 on the occasion of the seventy-fifth anniversary of the school. But then more openly I was very much interested in how chemical engineering developed. I'm not quite sure how electrical engineering has developed, but chemical engineering passed through a series of transformations. In the very early days, in the beginning of the century, it was more of an industrially-based field, driven by the knowledge of specific chemical processes.

Absolutely. A student in 1910 or 1920 would be well versed in organic chemistry. That was a major field then. The students were expected to memorize or know by heart, for example, how sulfuric acid or ammonia was produced.

Around 1925, especially with some very innovative educators at MIT, the field changed and became much more quantitative by the introduction first of thermodynamics, then of a series of other courses that translated the basics of chemical engineering into unit operations. These were units that can be identified not only in one process in chemical engineering, but in a variety of processes, like distillation, extraction, and crystallization. That kind of approach went on for about twenty-five years, and really changed the field. It made chemical engineers more “quantitative”.

Then, around 1955 there was another major change in the field. We became much more mathematical than before with the introduction of what we call “transport phenomena”, that is, fluid mechanics, heat and mass transfer. And with the introduction around the same period of applied mathematics in chemical engineering, there was another major transformation of the field. So when we start analyzing what has happened in the field we are fascinated that there have been all these changes.

Nebeker:

That was in a way good preparation for the computers, which became widely available in the ‘60s and ‘70s.

Peppas:

Absolutely. Don't forget, chemical engineers are in a very pivotal position to interact with other disciplines, and that has led to the significant introduction of bioengineering, not only in the curriculum but in our research.

I am going to comment on your question about computers. We find ourselves very well prepared right now to contribute to a major area of bioengineering called metabolic engineering, because chemical engineers have an exceptional background in computers and in understanding cells. The result is that the chemical engineers have “jumped” into the area of metabolic engineering trying to understand how metabolic processes can be optimized. This is only one of many areas that I can suggest where the chemical engineer has contributed because of his or her background—the mathematical background and the physicochemical background.

Undergraduate studies, National Technical University of Athens; fellowship at MIT

Nebeker:

If we could return to your own story of when you were educated there in Athens.

Peppas:

I received my first diploma at the National Technical University of Athens in 1971, and immediately I received a fellowship from MIT. So I left and came to MIT in August of 1971.

Nebeker:

What was your interest at that point?

Peppas:

That's very interesting. Before I left Greece, I knew that I wanted to do something new, original, and unusual, and something that eventually I could return back to Greece and practice it as a pioneer in the field. I identified the area of biomaterials and biomedical engineering, which in the late ‘60s did not exist in Greece. I always liked medicine, but in Greece, like many other countries, medicine is a professional degree, and one cannot take medical courses unless he is a student in the medical school. So, there was no chance for me to take pre-med courses of the type we have in the U.S. When I came to the United States I selected to work in that particular field. I selected to work with Ed Merrill, who was and still is the pioneer of biomedical engineering within the ChE field.

Nebeker:

Do you know how you originally thought that this would be a good area for chemical engineering?

Peppas:

I could see already in the late ‘60s that biology was becoming an important subject for scientists and engineers, that the field was changing much more towards biology. I had read a few nice articles in Scientific American and a few other journals talking about the artificial heart project, the artificial kidney project, and so on. I was already titillated.

Nebeker:

So you thought that chemical engineering offered certain things to that area.

Peppas:

Absolutely, because of our strong background in mathematics and transfer phenomena and flow behavior in materials. Of course, chemical engineers learn a lot about materials, more specifically polymers. So it was only natural for me to work in this field. So I came to MIT in August of ‘71.

Non-thrombogenic biomaterials research with Ed Merrill at MIT

I knew of the work of Ed Merrill. I started working with Ed Merrill immediately. Ed Merrill did his undergraduate degree at Harvard in Latin and Greek literature, and was also taking chemistry at the same time. There is this fascinating story about how he made a mistake one day, and entered the wrong classroom where a visiting professor from MIT was talking about chemical technology. He was either a junior or senior. He was fascinated, and decided, after he finished his Bachelor of Arts, to transfer to MIT and do a PhD there. It is a very interesting story about how he became a chemical engineer.

Nebeker:

So he appreciated your background.

Peppas:

Oh yes, that's right.

Nebeker:

What did you work with him on?

Peppas:

We worked at MIT in the very early days of biomedical engineering. We started developing a series of materials that could get in contact with blood and would not cause blood clotting. Therefore, they could be used for artificial organs. These materials are known as non-thrombogenic biomaterials.

Nebeker:

This would be like surfaces?

Peppas:

Surfaces, but these surfaces are modified with the appropriate utilization of anti-clotting agents, which in this particular case were heparin. So we were really the originators of the earliest heparinized materials that were used in catheters, in artificial kidneys, and to some extent a little bit later in artificial hearts, although we were not directly contributing to this.

Biomedical research funding and curricula

Nebeker:

Was the artificial kidney thought to be important?

Peppas:

The artificial kidney was a major problem of the period from 1962 to about 1975, and in fact, Ed Merrill was one of the major researchers in that particular field. So we were working with the support of the National Institutes of Health. As I am pretty sure you know, that was a very nice period for the medical field. Engineers could enter the field and suggest new solutions to problems or even provide solutions to mechanisms of diseases, and they would get significant funding from NIH. Things were going very well then.

Things changed later. Around 1976 or ‘77 there were some significant changes in support of biomedical research. But anyhow, Merrill and others at MIT had significant funding and it was a very productive period with significant interaction with Harvard Medical School. These were the very early days when MIT was trying to find a way to integrate biology into its program. So the way they did it at that time was in collaboration with Harvard. They had developed courses that students from MIT or Harvard could take. I remember taking biomaterials from Eugene Stanley, a major figure in the field, and artificial organs from Ed Salzmann at Harvard Medical School. We were allowed to do that at that time.

Heparinized materials research; Ph.D.

Nebeker:

What particular effort were you working on for your PhD?

Peppas:

That was the work of the heparinized materials. I was one of several individuals that developed a new series of heparinized materials to be used for artificial organs; the materials were eventually patented. But it was basically a series of studies of the synthesis, preparation, characterization, and study in contact with blood.

Nebeker:

Is this a type of materials that you have continued to do work on?

Peppas:

We continued working for about ten to fifteen years on such materials. I abandoned this type of work around 1985 because of other interests that I developed in the meantime.

Ed Merrill is really one of the last few Renaissance men, at least in the biomedical engineering field, so it was really magnificent to work with him. He was a person that could see the future, see what the needs were in the future, identify the need, give specific directions about how a problem should be solved. Then he would leave you alone to do your research and come up with the answers. He has graduated about seventy PhDs. Of these, about twenty-five or thirty are professors right now including some truly major names in the field. So he is really one of the pioneers in the field.

Nebeker:

Who else did you interact with there in those years at MIT?

Peppas:

Several individuals who were well known professors, but not so much in biomedical engineering. Interactions in biomedical engineering were taking place of course with Ed Salzmann, who was at Harvard Medical School and was another major figure in blood thrombosis. Then, there were interactions (especially because I stayed on as a post-doctoral fellow) with another group of individuals who headed the Arteriosclerosis Center.

Post-doctoral biomedical engineering work; arteriosclerosis

Peppas:

So immediately after I graduated with my PhD, I decided that I really wanted to get more involved in biomedical engineering. My work was about understanding the mechanisms of arteriosclerosis—how arteriosclerotic plaques form as a result of the flow of blood and components such as cholesterol and lipoproteins in the blood.

Nebeker:

At this stage it’s a matter of understanding the mechanism of that disease?

Peppas:

Absolutely, because once one understands the mechanisms of the development of the arteriosclerotic plaques one can find better ways of therapy and of treatment. So a good understanding of the flow behavior of the transport mechanisms into the aortic wall is very important.

Nebeker:

How did that work compliment or overlap with the traditional medical investigations of atherosclerosis?

Peppas:

Even in those early days of arteriosclerosis, medical doctors and engineers would work together. I remember we would talk extensively to medical doctors, identify what problems they had, what specific observations they had noted, and then we would try to come up with a similar experiment in an animal which would identify the exact mechanism of the development of the diseases.

Nebeker:

I've heard it said that the traditional engineering approach would be quantitative modeling of the phenomena, and the traditional medical investigators wouldn’t so much.

Peppas:

Yes. First the approach taken in the Arteriosclerosis Center was a little bit different. The experiments were a very integral part of that work. Modeling was an important part of our work, but cellular studies or tissue studies or transport studies were also important parts.

So, to go back to how we had approached the problem. At that time we were doing studies on white rabbits in which we were injecting specific amounts of cholesterol or lipoproteins, because low density lipoproteins are the carriers for cholesterol. Those low density lipoproteins had been labeled with a radioactive material. We were running an experiment where we would inject the animal with this particular compound, and the experiment would last a certain amount of time. At the end of that period we would sacrifice the animal, opening up the aorta, slicing the aorta to determine the concentration of cholesterol in the aorta. From these data we profiled the aorta. Of course, using our models we were able to identify what diffusional process had taken place and whether other processes had taken place at the same time.

Nebeker:

And so this differed form a traditional medical investigation in the quantitative understanding of the diffusion process.

Absolutely. A quantitative understanding was very important. At the same time, researchers like Bob Nerem (then at Ohio State and now at Georgia Tech) were in the early stages of their careers, and they would look more into the flow characteristics of arteriosclerosis. They were interested, for example, in how the flow behavior of the blood itself was affecting the deposition. So a mechanical engineer was seeing it a little bit differently than a chemical engineer, but all the results “came together”.

It's important to appreciate that the biomedical field is such an interdisciplinary and cross-disciplinary field that good training is very important. I'm delighted that I did post-doctoral work at that time. But it was only one year. It is not unusual to have biomedical engineers who spend two or three or four years, especially learning new cellular techniques or getting into genetics or into gene therapy. So postdoctoral work has become a “must” for the field. In classical electrical engineering or chemical engineering you can have students who become professors immediately after their PhD degree. But in biomedical this additional work is needed.

Nebeker:

So that was ‘73 or ‘74 you were at that post-doc?

Peppas:

Actually ’74 or ‘75. There is a small period in 1973 after I finished my PhD that I returned to Greece to do my military service. Therefore, at the end of the post doctoral period I felt that I was prepared enough that I could really make the big jump into academia, and it was a very nice period to interview at that time. There were numerous openings that year. I remember I took twelve trips to universities.

Nebeker:

But typically it's difficult when you are in a new field like that because few universities have a program.

Peppas:

It's possible. At that time I had a reasonably good curriculum vitae already. I believe I had about eighteen papers at that time, so people were willing to listen and to talk to me. I interviewed quite a few places in the Midwest, the West Coast, and the East Coast, but something attracted me to Purdue. It was obviously an excellent engineering program and the dedication to the ideas and to the programs that I wanted to develop, which were in the biomedical engineering field.

Nebeker:

Did you identify others here who were doing this work?

Peppas:

When I interviewed I did not meet Dr. Les Geddes. Geddes had arrived in Purdue in 1974. I interviewed in March of ’76, and he had just started his Biomedical Engineering Center. For me there were excellent veterinary medicine facilities at Purdue and in the medical school at IU, and that was a certain attraction.

Balance of theoretical and modeling work; experimentation

Nebeker:

So experimental work was definitely something you wanted to do?

Peppas:

Actually it was a balance. I mean theoretical and modeling work was and still continues to be a part of my effort.

Nebeker:

Have you continued to work with animals, animal experimentation?

Peppas:

Yes. The way I have done it recently is “to farm the studies out” to other units or universities. I do some of my experiments, with a colleague in biomedical engineering, Steve Badylak. I do some of my studies in veterinary medicine, and then I have subcontracts to other universities. For example, right now we have a major study for a new oral delivery system for insulin where all the animal studies are conducted out of the Thomas Jefferson Medical School in Philadelphia. They have a subcontract from us through NIH to do these studies.

Research, publication, and teaching at Purdue

Nebeker:

What was your work when you first came here to Purdue. What was your main reason for coming?

Peppas:

The early work was somewhat routine. We started in 1976 with the improvement of certain types of biomaterials that we had already developed at MIT, further improvements of such biomaterials for the artificial heart, for the artificial kidney, and so on.

Nebeker:

Were you working with another faculty member?

Peppas:

I liked to be alone in the development of such systems, and for many I was able to do that. There were interactions with other departments, though.

Nebeker:

The papers in that period were authored by you alone?

Peppas:

Yes, and the students.

Nebeker:

You had graduate students from the beginning?

Peppas:

Purdue University attracts very good graduate students. I arrived here in 1976 and already in the first Fall I had four students. By 1978 my group was at about a level of about twenty PhD students and MS students and technicians When you asked me the question about how we were working, what I was trying to point out is that we did not have any formal interactions with another entity. Of course, we were using their knowledge and we would use the facilities but in the beginning there was no collaboration.

Nebeker:

I know many biomedical engineers have worked with somebody in another department.

Peppas:

In the early days I concentrated on biomaterials. I had the background and I knew what I wanted to do. By 1979 a very serious interaction developed with Professor Alan Rebar in the veterinary medicine school. Rebar has now become the Dean of Veterinary Medicine. This was the time that we were doing the first systematic studies to identify the response of these materials in non-thrombogenic applications.

At the same time Dr. Geddes had arrived from Baylor. He had started a Biomedical Engineering Center. Originally, I think, the idea was that the Biomedical Engineering Center was going to become a university-wide entity and it was going to include everybody who was a biomedical engineer. Well, it didn't work out that way.

Geddes was extremely successful in his early studies in defibrillators, and that led to his developing the Center for himself and his associates. So, the interactions with the rest of us were minimal. The interactions would be mostly of the sort of him calling me and saying, “Do you have a material for this application?” but that was about it. They were a very active group, but perhaps working by themselves—and very much in the development of new devices.

Nebeker:

It is such a vast field.

Peppas:

Absolutely.

Freezing and thawing of biomaterials

Nebeker:

I also wanted to hear about the 1975 contribution of the freezing/thawing technique of biomaterials.

Peppas:

In the very early days of our contributions to biomaterial science, one thing that became very obvious was that the biomaterial itself was not toxic. What created the toxicity was a series of unreactive monomers, adjuvants, stabilizers, and other compounds that were added to make the system more stable, as well as a variety of other chemical compounds that were needed in order to “solidify” the material. So in the very early days I became interested in coming up with alternate ways of preparing materials without using toxic compounds. That led to the very early studies of benign manufacturing of biomaterials.

Nebeker:

This is a field now?

Peppas:

It is the field of benign manufacturing of biomaterials and biomedical devices. By serendipity I discovered in 1974 that if I take a solution of a particular biomaterial and freeze it and thaw it several times I can create a solid structure by a process of solidification that requires entanglement of the macromolecular chains and at the same time formation of crystals. It doesn't work for any material, but it does work for a rather wide range of biomedical materials. Some of the early studies were done in 1975, the year of the first paper, and the patents were filed. Over the last twenty-five years such materials have been used for a wide range of applications, mostly in the drug delivery field, but also as medical coatings.

Nebeker:

So it makes me think of the very early days of making good electric batteries, the formation that was required, the charging-discharging-charging many, many times. How did you get the idea of this repeating freeze and thawing?

Peppas:

I do not remember all the details, but I think it was mostly my understanding that when one crystallizes a material the crystals themselves act as "tie points" that will not allow the polymer, the material, to dissolve. So I sought ways to crystallize. Well, we crystallize usually by raising the temperature. We couldn't do that for most biomaterials. But low temperature heating is still a crystallization process, but a much slower process. So I tried first with cooling at 4oC, and then at 0oC, and then at -20oC. Surprisingly enough, after two or three of these cycles I noticed that the material was remaining solid and it was not flowing. It was very natural to continue that way.

Nebeker:

And this is found to be very important?

Peppas:

It has very important applications in contact lenses, in vocal cords, and of course more recently in drug delivery systems—a variety of drug delivery systems for transdermal applications.

Nebeker:

Why were you trying to crystallize this?

Peppas:

Because somehow the liquid had to solidify and remain solid and not flow over a long period of time.

Nebeker:

Without the addition of these agents.

Peppas:

Chemical reactions would have been the only way to do it. I was trying to deviate from any possible chemical reaction.

Nebeker:

To get a benign material.

Peppas:

A benign material, exactly. That’s how it led to that. In the very early days at Purdue this was really a serious development, the development of this freezing and thawing system. Another one was the development of materials for reconstruction of vocal cords. This was really a very significant problem at that time, and it still is, because there are patients who suffer from atrophic conditions of one or both of their vocal cords. We know of cases of epileptic patients, who through some kind of accident have cut their cord. Of course we have situations of aplasia, which means total lack of one of the cords. Finding better ways to reconstruct the vocal cords was really a major goal at that time.

Nebeker:

But that was something that was being done at that time, reconstructing vocal cords?

Peppas:

Yes, but in very, very primitive ways. I remember in 1975 when I visited the clinic with which we were interacting in Chicago that the way they were doing it was by injecting a solution or a suspension of paraffin into what had remained of the vocal cord—paraffin with little pieces of bone! It was really a very primitive way of reconstructing the vocal cord. We came in with gels that were non-toxic and non-carcinogenic that could be injected and then solidify in situ. So that created, of course, a totally new solution to the problem.

Nebeker:

That worked?

Peppas:

It did work. For a decade it was used in various hospitals in the United States and in Europe until better systems were developed. So in the very early days our efforts were non-thrombogenic biomaterials, so that when the blood came into contact with them it would not clot; vocal cords; this new system of freezing and thawing that we were talking about; and some work on articular cartilage. Basically, if we tried to analyze what we were doing, we had very good gels that had certain properties and we were trying to see where we could apply them in the body to replace certain worn organs.

Nebeker:

How did you get onto these gels, this class of gels?

Peppas:

Through my Ph.D., my background in polymers, and my background in materials. It was only natural.

No, they were not the same gels. They were modifications. They were new systems and new classes of polymers. Already in the mid-seventies we had starting looking very seriously at how to design such systems from first principles. We started looking at whether there are certain characteristics of these gels that could be replicated—whether there were certain chemical structures that would lead to more desirable gels.

Nebeker:

So, you were sort of exploring this material and seeing how it can be useful medically.

Peppas:

Absolutely. Today you would call it combinatorial chemistry. It was not done as combinatorial chemistry in 1975, but there was definitely a plan. My students and I had identified certain properties that we wanted to achieve and certain characteristics that a material had. We knew that this functional group would contribute to that property and the other functional group to the other property. So we were going to go through a permutation of different functional groups that must be in a gel in order for it to behave in a particular fashion.

Nebeker:

So it is really engineering and not exploration.

Peppas:

No, it is really engineering. In fact, then and now, the students who decide to work in our laboratory are trained first and foremost as engineers, not as chemists. Yet, chemistry is an extremely important part of our work.

Nebeker:

What I mean is one might imagine that all one can do is try altering the properties of gels and hope that you get the right thing. But you say you understood how to create certain effects and properties.

Artificial kidney development; interdisciplinary collaboration

Absolutely. Then I think another major milestone in our development as a group here in biomedical engineering was in 1978. In 1978 a young researcher/medical doctor by the name of Steve Ash had just arrived in the town. He arrived from the University of Utah where he had studied with one of the fathers of biomedical engineering, Wilhelm Kolff, in the artificial kidney program. When he came here he established a kidney program. I don't remember his association with Purdue. I think he had an appointment in Veterinary Medicine, but he was working in the Biomedical Engineering Center. He established a product to develop an artificial kidney that would be portable or wearable. If you recall, what was happening with artificial kidneys in the ‘60s and ‘70s is that a patient would have to go to a hospital, lie on a bed, be connected to a dialysis unit. This unit required all this water in order to take away the urea and uric acid. That process would take four hours every second day.

So, Steve's idea was, “Can we come up with a portable artificial kidney?” He got money from various sources including some companies, and for a period of about five years we had a tremendous development in that particular area. I was developing the biomaterials that were used in this artificial kidney.

At the same time I got much more into the artificial kidney as a biomedical engineer identifying flow behavior and transport phenomena. I can tell you the kidney worked very well and it was sold to a small company that was created. Now they are in the second generation of systems with artificial livers. One of the functioning artificial livers available right now is coming from a small company in Lafayette, Indiana, which was one of the companies that Steve Ash founded.

That was the second development because now our group became much bigger and interactions with other programs started. We had interactions with the Biomedical Engineering Center, with veterinary medicine, with biochemistry, and with biology—every discipline that is needed in order to create a true cross-disciplinary program.

Nebeker:

So, you were just summarizing the early work?

Peppas:

So between 1978 and about 1982—in 1982, actually—this additional development of the artificial kidney contributed to our becoming much more cross-disciplinary, finding our way within Purdue, and becoming more internationally known. I became a full professor by 1982, so in six years I had covered Assistant, Associate, and Full professor appointments. Not that it makes any difference at Purdue. At Purdue you are free to work the same way whether you are an Assistant or an Associate or a Full professor. But it made a difference for me because I could really start my long-term projects and cultivate my ideas for the future.

Editing Biomaterials

Nebeker:

Also, in 1982 I know you started as editor of the new Biomaterials.

Peppas:

It’s considered to be the premier journal of the field and was started in 1980. From day one I was asked to be on the editorial board. In 1982 I took over as editor, and I am very proud for what we have done with this journal. It’s been eighteen years now and we publish now about a thousand pages a year. Some of the best papers in biomaterials are published in this journal.

Nebeker:

And it tries to cover all types of interests.

Peppas:

It not only tries to cover but tries to give new directions in the field. For example, you see, we were publishing work on tissue engineering as early as 1988. Twelve years ago, when tissue engineering was still a very “strange” area-- How can you create new tissues? So, it has worked very well for us.

Drug delivery research

I want to make a few comments about biomedical engineering as well, but since you really want to know what happened here at Purdue, let me talk about how in my own scientific life there was another development that created the stage for what came after 1982.

In 1978, I had a post-doc who came from Switzerland, Robert Gurny. Robert came to the United States to work on learning about biomaterials and polymers. He was a pharmaceutical scientist and he could see that biomaterials could be used in drug delivery. I knew about drug delivery but I had never really worked in the field. With the presence of Robert Gurny here, my interest in drug delivery became more serious. People in the biomedical field are using materials to deliver drugs to specific sites of the body. Now, this is a very easy thing to do if you are going to deliver drugs, let’s say, to the eyes or the nose. But it is much more difficult if we are going to deliver drugs internally to a specific organ, for example, to the upper small intestine where the absorption of the drug is the highest or when we want to target the drug to specific cancer cells and tissues.

The presence of Robert Gurny here for two years led to a significant expansion in this particular area. I'd say that we started the most important development of drug delivery as early as 1979. As you probably know, this group is considered one of the foremost groups in the field because we have combined biomedical engineering principles with a good understanding of modeling. We are known for the mathematical developments in that area and, at the same time, a good selection of materials and development of new devices and systems that are used for delivery not only of drugs but also of consumer products.

Robert Gurny was from the University of Geneva. When he returned to Geneva he suggested that I take a sabbatical leave, and in 1982 I took my first sabbatical leave. I went to the University of Geneva, and it was really beneficial because finally I had some time to sit down and develop my vision for the future. This led to all the new work that was done over the next eighteen years (after 1982).

Nebeker:

Were the gels you had been working on earlier something that could be applied to drug delivery?

Peppas:

Not these particular ones; there were different modifications. In 1982-1983 we started working with smart gels and smart materials. There is nothing “smart” about them except that they have certain functional groups that interact with a surrounding environment in a particular way. For example, we know that if we have certain functional groups such as carboxyl groups, these groups in a low pH environment will not be ionized while in a high pH environment they would be ionized. What this means is that the gel in a low pH environment would stay collapsed while in a high pH environment will expand. That can be used to our advantage to create switches—biomedical on-off devices to release drugs, to release proteins, to push valves and to push molecular pistons. We started with these smart materials around 1982, which have become a major part of our work. It is interesting that smart materials were developed predominately in Japan. Since these early days we had significant interaction with Japan, so it was only natural to be involved in those developments.

Sabbaticals and collaboration with Japanese researchers

Nebeker:

I saw that you spent a number of periods in Japan.

Peppas:

Sabbatical leaves for me are very important and I take them very seriously. They are very important because they make me rethink and redirect our work. The interactions with other countries have been very helpful to me. In 1982 I was in Geneva, and then I continued for half a year at Cal Tech. In 1986 I was at the University of Paris XIII. Then I visited the University of Parma and the University of Pavia. Then, in 1994 I went to Hebrew University in Jerusalem and the Hoshi University in Japan.

The interaction with Japan has been going on for about ten years, and we have Japanese coming here and students from Purdue going to Japan spending a month or two always supported either by a grant or by some special funds. Purdue University, for example, has a program called the internationalization or globalization grants program. They contribute about $5,000 for a graduate student to go to another university abroad to do studies and learn something new. We have had several of these grants. So 1982 really was a very important year for me because I was a full professor after six years at Purdue and at the same time I had started all these interactions with other countries.

I work predominantly with graduate students and some post-docs. I don’t have Assistant professors and I don’t have Associate professors work under me. Maybe I'm too classical in that. I like to work with the students and with the post-docs directly. Our system here at Purdue, at least in chemical engineering, does not allow an Associate professor or an Assistant professor to be a subordinate of a full professor.

Nebeker:

This group was you with post-docs and grad students?

Peppas:

Absolutely. Always on the second floor plus another building plus the animal studies, and always supported by NIH, the National Science Foundation (NSF), some industrial grants, and some other organizations like NATO. But always very good funding. Funding has never been a problem. Typically, we had two to three NIH grants at the same time and one or two NSF grants. So my group of thirty researchers includes Ph.D. students, post-docs, honors students (the students who are basically getting their bachelors degree, but they have to spend a whole year to do a thesis), technicians, and visiting scientists. The interactions with other countries and other universities led to a lot of visiting scientists—individuals who come here to spend some time with us, typically six months to a year, paid by their governments.

So, in 1982 we started this expansion in the various aspects of drug delivery, without forgetting biomaterials, of course. The result was that within a short period of time we had come up with new designs and systems that could be used in the physiological environment and would respond to pH or temperature.

Nebeker:

Were you working with any companies?

Peppas:

Yes, several companies over a long period of time. We had collaborations with maybe ten to fifteen companies. Also, the field of drug delivery and controlled release, which is a sub-field of biomedical engineering, was relatively young.

Some major diseases can be treated only with protein drugs. For example, insulin is used to treat diabetes. Diseases such as multiple sclerosis are treated with interferon beta. Some forms of cancer are treated with interferon alpha; dwarfism with growth hormone. All these diseases are treated by genetically engineered proteins, which are delivered in very small amounts. They can be delivered to a specific site where they will act. In the last twenty years the field has been very dynamic and has required a good understanding of targeting, or direction to the specific cells where the drug has to be delivered. This provides conditions that will not affect the protein’s ability, because if a protein is unstable it will not act. It is very easy, for example, to come up with an oral delivery formulation for insulin, except that by the time insulin passes in the blood it would be inactive. So, that is not really the goal of present research.

In general, our field has become very demanding. Biomedical engineers need to have a much better understanding of cellular behavior. So if you really look at chemical, biomedical, and mechanical engineering, you will see that cells have become a very important part of the overall work.

Nebeker:

Do you think that since this field is large that you have had real success in being able to deliver proteins?

Peppas:

Well we think so. Yes, there have been some very major developments in the last few years, which have led to commercialization of some truly successful products.

Nebeker:

It must be an interesting field to be in because of the commercial potentialities of it.

Peppas:

Yes, you are absolutely right. At the same time this creates numerous questions about ethics, about conflicts of interest. I would be glad to share with you my philosophy. Our main goal in a university should be the education of our students. We should be using research as a way to teach them how to solve problems, and at the same time we should be doing research to solve problems, identify processes, identify biological mechanisms. If the development of a device or a product comes as a result of it, so be it. But I strongly disagree with a portion of the academic world that uses the university environment to develop medical devices in order to create new companies.

A prevailing attitude in American universities is that the only way for American universities to succeed is by interaction with industry. We have a major debate of whether professors should be hired and given laboratory space, given facilities for the sole purpose of creating new products.

I still believe the university has a main goal of educating people. Another educational approach is that the university should be a place where we should train students for industry. I believe we should educate students, we should educate people, and we should make them solve problems at any level.

Nebeker:

Right, but nevertheless, you must have this feeling that this is potentially very valuable.

Peppas:

Absolutely. For me the most important feeling is that what I do is very valuable and can be used to solve a medical problem. For example, when we were working in the late ‘70s on artificial cords, and when I saw our first gels being introduced and injected in patients and we could see those patients ten days later speaking with a voice that was much more natural, that was a major satisfaction for me and my group. Or, when we know that some day a diabetic patient who takes injections would not need to take injections and would instead be able to take just a pill or a capsule, this is a real satisfaction.

Now, did we file patents? Not only at Purdue University, but also at any other major university, when one finishes something original one files a disclosure. Typically the disclosure is done to the technology transfer office of the university. It doesn't have to be a very long document. It can be a few pages long, indicating what has been discovered, what is new, what type of companies might be interested in.

Then with this disclosure, the university can approach companies and ask for signing of a confidentiality agreement? Another possibility is for a professor and/or the university to start a small company. Start up companies are becoming now a major part of the university's activities.

Nebeker:

It's all been seen as a measure of how productive you are at creating spin-offs.

Peppas:

Of course. But if a professor leaves his office for two days and goes to his company because he has to supervise what is happening at the company, then something is wrong about the system. That has been my concern over the years.

Drug delivery and biomedical engineering milestones

Nebeker:

Could we return to your main areas of work? I guess we are into the ‘80s.

Peppas:

Our early studies on drug delivery were around 1979. The major developments came around 1982 and have been going on for the last eighteen years. There is another group that is considered the best group in the world by some, not only in drug delivery people but also in biomedical engineering in general. That group started working at about the same time, and I happen to know them very well. It is the group of Bob Langer at MIT. He worked as a post-doctoral fellow with Judith Faulkman at Harvard Medical School. He contributed to angiogenesis.

Then in 1977, he started as an Assistant Professor at MIT in the Department of Nutrition and Food Science. What would a biomedical engineer do in such a department? He was allowed to do applied biological research. Bob had his own ideas about protein delivery and about artificial organs. Within a period of about four or five years, he had established a very important position in the field of protein delivery, purification of blood from impurities using enzymes, and other areas. You might wish to talk to Bob Langer or at least talk to some of his associates, because he has had a tremendous impact in biomedical engineering. He has published about six hundred publications and filed three hundred and fifty patents. He has started several biotech companies, and he is the most innovative researcher in the field. He is the only active member of all three academies in the United States: The National Academy of Sciences, The National Academy of Engineering, and the National Institute of Medicine. I would definitely consider him as a pioneer in the field and somebody who has taught us "how to think".

My interactions with Bob started in 1979, and I have been helped very much by the way he thinks. We have exchanged students, we have written papers together, we have written books together.

Nebeker:

It's very pleasing to me to hear how it seems there is not only this sharing within the United States but with universities around the world in a field where you might think there would be more secrecy and competition because of the commercial potential.

Peppas:

You are right. I agree that some individuals do become competitive and act in a competitive way. This has not happened with most of us, and I don't know to what to attribute this.

We were the first generation of engineers that were educated as "biomedical engineers". Naturally, we respected each other and we wanted to support each other. I don't know how the next generation of BMEs is going to behave. Maybe they will be become very competitive, as you said. Maybe they will become as competitive as biologists are right now.

But to return back to the ‘80s, during that period our group increased. Funding was really significant. It was at that time that we made a decision for the future, the results of which I think we see now. I started putting the foundations of molecular design. There was no way for us to develop better drug delivery systems or improved therapeutic devices without a true molecular design. It was important to go back to the principles and try to understand the molecular structure that creates a particular property, and whether the material can release a particular protein very fast, or the ability of the material to adhere to a particular surface. We were able to come up with a series of papers in which we defined how molecular design could be used in these new biomaterials and drug delivery systems.

Molecular design of biomaterials; combinatorial chemistry

Nebeker:

This field is called molecular design?

Peppas:

Molecular design of biomaterials. There are several groups working in this area. Now, combinatorial chemistry contributes to the next generation of biomaterials.

Nebeker:

By combinatorial chemistry do you mean trying to find the best material?

Peppas:

Yes. Of course, this has been followed by cellular studies in order to verify the approach. There were mostly successes, I must say, but some failures as well. Among the successes of the field is the development of a category of materials that is quite interesting to us, the muco-adhesive and bio-adhesive materials

These biomaterials can adhere to particular sites in a specific way and remain in contact with these sites for a period of time. This is done for various reasons, as for example, to make materials that act as temporary wound closures, or to prepare materials as carriers for protein delivery to particular cells.

We started research in this field during my sabbatical in Geneva. We worked at the University of Geneva with a very dear colleague, Professor Pierre Buri. We initiated a series of experiments in 1983 and learning together about bio-adhesion. Eighteen years later this has become an important subject in the field.

Oh, yes. In the ‘80s all this work continued: the pH-sensitive systems, the smart hydrogel systems, and the temperature-sensitive systems.

Establishing biomedical engineering department at Purdue

Peppas:

In the early ‘90s, I was appointed the Showalter Distinguished Professor of Biomedical Engineering, succeeding Dr. Geddes. As the Showalter Professor, I tried to bring together all the biomedical engineers that existed on campus working in different departments and biomedical engineers who “did not have a home”. We started a series of seminars and initiated the preparation of major research proposals. Eventually, in 1998 we formed the Biomedical Engineering Department.

After significant effort and discussions it was decided that this biomedical engineering program was going to be a joint effort between the Schools of Engineering at Purdue, the School of Engineering at Indianapolis, the IU Medical School, and the Veterinary Medicine School. The first nucleus for this effort was at the end of 1993. Instrumental in this effort was Professor George Wodicka, a young MIT graduate of the Medical Engineering program there, who took the initiative to help in the formation of the program. So George Wodicka was selected to be the first Head of the new BME Department.

The first thing we had to achieve was to receive permission by the State of Indiana to offer a Ph.D. degree in biomedical engineering; this was done in June 1996. The Department of Biomedical Engineering was started in 1998. We have about fifteen faculty members and forty Ph.D. students already. We have received a Whitaker grants, and also we have some “unusual” programs. One of these is an interdisciplinary program in the area of Therapeutic and Diagnostic Devices that is supported by the National Science Foundation. What is unusual about this program is that the students must have at least two major professors coming from “dissimilar” research areas.

Nebeker:

So, this is specifically a program to tie different areas together?

Peppas:

Exactly, to tie them and bring them together. NSF supports these types of programs. In our program, for example, somebody from pharmacy and I can have a joint student. The student's education is really a result of these efforts and different courses. We offer core courses and we have laboratory modules that the students must take.

It has been a very successful program. We have eighteen Ph.D. students taking it. Their tuition fees are paid and they get an annual salary of $19, 000 a year. They are paid $5,000 for supplies and expenses and paid to participate in meetings. As you can imagine, it is really a very successful program. It’s the first program of that nature in the country, and NSF has supported twenty programs with the same mentality, but in different areas. For example, Wisconsin has a program in limnology, or lake sciences, while Harvard has a program on public policy. So, they can be in different areas.

Biochips and bionanotechnology

Peppas:

Recently, we have also embarked upon new areas of biomedical engineering. We are working on biochips, and bionanotechnology.

Nebeker:

Are these chips silicon chips?

Peppas:

They could be silicon-based. The ones we have are methacrylate-based. In fact, we use the same type of micro-lithographic techniques that could be used for integrated circuits. The work is performed in electrical, biomedical, and chemical engineering. This shows how these areas merge together.

I think that in the next twenty years nanotechnology and bioengineering will merge. I really think we are leading towards more miniaturized devices. I tell my students that in 1950 an artificial kidney was a big hospital unit, to which one had to be connected for four hours. In 1980 or 1985 the kidney was a unit about thirty centimeters long and often portable. Don’t you think there will be a progression and that perhaps by 2020 it will be replaced by a small box with a few “chips”?

In a related application, Bob Langer at MIT has developed microchips that can release up to 200 drugs at different levels, triggered by specific inputs coming from the body. Actually, they have formed a small company called MicroChips to commercialize this particular invention.

Nebeker:

So, this would be a coming together of the electronics field and drug delivery?

History of the biomedical engineering field

Nebeker:

You said earlier that you had some general comments about the field of biomedical engineering. Maybe you have already expressed this.

Peppas:

Biomedical engineering is a mature field now. It is reinventing itself to some extent, but it is a mature field. The beginning of biomedical engineering goes back to 1942 in Amsterdam when Wilhelm Kolff was the first who developed an artificial organ to dialyze animals. Later, Kolff came to Cleveland Clinic and then the University of Utah; the artificial heart of Jarvik came out of his group. Kolff is now in his nineties and is retired.

Over the last fifty or sixty years, we have seen is integration of biology with mathematics along with an understanding of flow behavior, transfer properties, electrical circuits, and biomechanics. We cannot forget that cells are important components of the biological systems. Those of us that are somewhat older and want to be active in the biomedical field, we need to be better educated in cellular engineering.

Nebeker:

Do you see a danger in this computer modeling of everything?

Peppas:

I think that in all new Biomedical Engineering Departments, biology has to be an integral part of the education of students. If we really want to "produce" good biomedical engineering students, good graduates and successful engineers, we have to teach them biology from the beginning. That is what we try to do here at Purdue.

Nebeker:

Generally, I think there is very strong support among the public for medical research.

Peppas:

Absolutely. I don’t know if you heard about the latest bill that was passed in Congress creating a new Institute of Bioengineering and Imaging in NIH, which means that there will be additional funding for this type of research. Obviously, the Whitaker Foundation has done a tremendous job to "reestablish" biomedical engineering. The field continues to expand and more and more students want to become biomedical engineers. I think this trend is going to continue.

As I look back, at least at the chemical engineering aspects of biomedical engineering, I identify Ed Merrill as the father of this particular field. For example, he was the one who started the field of blood rheology. He was one of the early fluid mechanicians, and blood rheology was his first major "biomedical" research area. Then he got into the biomaterials and related biomedical fields.

After him, there were several pioneers. I showed you an article published recently by AIChE that mentions several of these pioneers. Alan Michaels, who just passed away, was a major figure in membranes used in biomedical applications. Alan Hoffman of the University of Washington at Seattle (in the Biomedical Engineering Department) is a major figure in biomaterials and drug delivery.

Among the younger researchers, Bob Langer, Clark Colton and Doug Laufenberger shaped the field. Bob Nerem is one who has done great work with the Biomedical Engineering Department at Georgia Tech. He is a mechanical engineer, but one who has kept this contact with chemical engineering so that we think of him as our colleague.

Nebeker:

I believe that the mechanical engineers had him on their top list of people to talk to.

Peppas:

Bob has been responsible for the establishment of AIMBE, the American Institute of Medical and Biological Engineers. It was his idea that there should be an organization that would bring together all biological engineers. He wanted to have all the influential biomedical engineers form a strong scientific lobby in Washington. I believe that the bill that was passed in Congress creating the new Institute of NIH is a result of the existence of the AIMB. Paul Galetti of Brown University was another pioneer.

There is another field that is related to bioengineering, a field where chemical engineers have contributed significantly, that of biochemical engineering.

Nebeker:

How is that defined?

Peppas:

It is the utilization of biochemical processes in order to produce desirable chemicals.

Another pioneer in our filed is Ed Leonard of Columbia University.

Nebeker:

He is also on my list.

Peppas:

He is a fascinating man. He will give you the history of medical devices. Ed is a good example of how medical doctors and engineers work together. In the early days of our field, and especially in the Boston/New York corridor, there were numerous engineers with interactions with the major medical centers, such as Harvard Medical School, Mount Sinai, or Sloan Kettering.. Individuals like Ed Leonard, Clark Colton, Mitch Litt of the University of Pennsylvania and others are really the chemical engineers who created the biomedical field.

In the ‘70s the biomedical field was flourishing. It was a great field to work in. This was followed by a period of reevaluation. In fact, in the 80s, several Departments of Biomedical Engineering simply folded.

Nebeker:

Is that right?

Peppas:

I know that many students were not able to get jobs. I remember my early graduate students indicating that they wanted to get my Ph.D. in chemical engineering, not in biomedical, just in case they could not find a job in the biomedical field. Things changed around 1985 because of Whitaker and because of our understanding of the importance of the field.

Nebeker:

Were there some achievements in biochemical or biomedical engineering generally that contributed to this?

Peppas:

Probably. I think all the publicity of the artificial heart in the 80s led to a very positive public reaction. Very public cases such as the accident of Christopher Reeves that paralyzed him, or perhaps the Alzheimer’s disease of President Reagan, have led to a significant reawakening of the interest of researchers to find solutions to such very important problems.